Abstract
This study was conducted to investigate the effects of oxytocin (OT) on visceral hypersensitivity/pain and mast cell degranulation and the underlying mechanisms. We found that oxytocin receptor (OTR) was expressed in colonic mast cells in humans and rats, as well as in human mast cell line-1 (HMC-1), rat basophilic leukemia cell line (RBL-2H3) and mouse mastocytoma cell line (P815). OT decreased 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced visceral hypersensitivity, colonic mast cell degranulation and histamine release after mast cell degranulation in rats. Also, OT attenuated the compound 48/80 (C48/80)-evoked histamine release in P815 cells and inward currents, responsible for the mast cell degranulation, in HMC-1, RBL-2H3 and P815 cells. Moreover, these protective effects of OT against visceral hypersensitivity and mast cell degranulation were eliminated by coadministration of OTR antagonist atosiban or a nonselective inhibitor of nitric oxide synthase (NOS), NG-Methyl-L-arginine acetate salt (L-NMMA). Notably, OT evoked a concentration-dependent increase of intracellular Ca2+ in HMC-1, RBL-2H3 and P815 cells, which was responsible for the activation of neuronal NOS (NOS1) and endothelial NOS (NOS3). Our findings strongly suggest that OT might exert the antinociception on colonic hypersensitivity through inhibition of mast cell degranulation via Ca2+-NOS pathway.
Highlights
IntroductionMast cells degranulate and release mediators that enhance the excitability of enteric and primary afferent neurons, leading to visceral hypersensitivity[17]
NOS1, inducible NOS (NOS2) and NOS3 have been found in human mast cell (HMC)-1 cell line, NOS3 has been found in rat basophilic leukemia RBL-2H3 cell line and NOS2 is expressed in P815 mouse mastocytoma cell line
This study demonstrated that OTR was expressed in colonic mast cells in both humans and rats and it was contained in HMC-1, RBL-2H3 and P815 cells
Summary
Mast cells degranulate and release mediators that enhance the excitability of enteric and primary afferent neurons, leading to visceral hypersensitivity[17]. Histamine is a major inflammatory mediator released from mast cells when they degranulate, which could activate visceral afferents[17] and enteric neurons[18]. We speculate that OT might suppress visceral hypersensitivity through inhibiting mast cell activation and degranulation. Some evidence has suggested the participation of nitric oxide (NO) derived from NOS in the inhibition of mast cell activation/degranulation[19] and histamine release[20]. NOS1 is expressed in 30% of human intestinal mast cells. Human intestinal mucosal mast cell (IMMC) express NOS1 and NOS3, while rat IMMC express only NOS321. We found that OT down-regulated visceral hypersensitivity in TNBS treated rats and inhibited mast cell degranulation. These preliminary data supported our hypothesis and provided new evidence that OT might inhibite mast cell activation and degranulation through activating NOS in mast cells
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